This application is directed to a method for combined therapy of psoriasis based on methods for decreasing the increased activity of phosphorylase kinase in psoriasis.
Psoriasis is an inherited skin disease, the causal mechanisms of which are still unclear. However, the disease is believed to have a strong genetic basis. (H. Baker, "Psoriasis" in Textbook of Dermatology (A. Rook et al., eds., 4th ed., Blackwell Scientific Publications, Boston, 1986), vol. 2, pp. 1469-1532). In fact, this has been confirmed by recent findings from genetic studies of psoriatic families (G. Lomholt, "Psoriasis: Prevalence, Spontaneous Course, and Genetics" (Copenhagen, Denmark, GEC GAD, 1963); E. M. Farber et al., "Natural History of Psoriasis in 61 Twin Pairs," Arch. Dermatol. 109:207 (1974)), which suggest that at least two genes are implicated in the manifestation of psoriasis in predisposed individuals (J. T. Elder et al., "The Genetics of Psoriasis," Arch. Dermatol. 130:216-224 (1994)). One of these has been mapped to the short arm of the 6th chromosome (J. T. Elder et al. (1994), supra), and the other to the distal end of chromosome 17q (J. Tomfohrde et al., "Gene for Familial Psoriasis Susceptibility Mapped to the Distal End of Human Chromosome 17q," Science 264:1141-1145 (1994)). Chromosome 6 contain genes encoding not only class I and class II antigens of the major histocompatibility complex, but also class III (tumor necrosis factor-alpha TNF.alpha.! molecules (J. T. Elder et al. (1994), supra). The expression of TNF.alpha. and its receptors has been shown to be enhanced in psoriatic skin (M. Kristensen et al., "Localization of Tumor Necrosis Factor-Alpha (TNF.alpha.) and Its Receptors in Normal and Psoriatic Skin: Epidermal Cells Express the 55 kD but not the 75 kD TNF Receptor," Clin. Exp. Immun. 94:354-362 (1993)), pointing to the possible role of superantigens in precipitating the disease (M. C. Y. Heng et al., "Erythroderma Associated with Mixed Lymphocyte-Endothelial Cell Interaction and Staphylococcal aureus Infection," Br. J. Dermatol. 115:693-705 (1986); B. J. Nickoloff et al., "Activated Keratinocytes Present Bacterial-Derived Superantigens to T Lymphocytes: Relevance to Psoriasis," J. Dermatol. Sci. 6:127-133 (1993)). Current investigations suggest that TNF.alpha., through its capacity to influence the expression of the nuclear proto-oncoproteins, c-myc (J. X. Lin & J. Vilcek, "Tumor Necrosis Factor and Interleukin-1 Causes Rapid and Transient Stimulation of c-fos and c-myc mRNA in Fibroblasts," J. Biol. Chem. 262:11908-11911 (1987)) and c-fos (M. Hendriksson et al., "Phosphorylation Sites Mapping in the N-Terminal Domain of c-myc Modulate its Transforming Potential," Oncogene 8:3199-3209 (11993)), which are known to be important in regulation of cell growth and differentiation (O. Baadsgaard et al., "UM4D4+ (CDw60) T Cells Are Compartmentalized in Psoriatic Skin and Release Lymphokines that Induce a Keratinocyte Phenotype Expressed in Psoriatic Skin Lesions," J. Invest. Dermatol. 95:275-282 (1990)), may be important in increasing the gene expression of phosphorylase kinase. This hypothesis is consistent with current concepts involving the role of cytokines and proto-oncogenes in the phenotypic expression of psoriasis (J. T. Elder et al., "Protooncogene Expression in Normal and Psoriatic Skin," J. Invest. Dermatol. 94:19-25 (1990); G. Sozzi et al., "A t(10.17) Translocation Creates the RET/PTC2 Chimeric Transforming Sequence in Papillary Thyroid Carcinoma," Genes, Chromosomes & Cancer 9:244-250 (1994)).
It has been suggested that increased phosphorylase kinase activity may be due to defective regulation or presence of multiple copies of sequences encoding phosphorylase kinase in the genome of the psoriatic individual. This explanation is unlikely since, of the protein moieties under consideration, only the gene sequences encoding the regulatory subunit of cAMP-dependent protein kinase II has been mapped to the 17th chromosome (P. J. Barnard et al., "Mapping of the Phosphorylase Kinase Alpha Subunit Gene on the Mouse X Chromosome," Cytogenet. & Cell Genet. 53:91-94 (1990)). On the other hand, none of the phosphorylase kinase subunits have been mapped to chromosome 17. Instead, the alpha subunit of phosphorylase kinase has been mapped to the X chromosome, where it lies between the genes encoding the X-linked zinc finger protein and phosphoglycerate kinase genes (P. J. Williams et al., "Mapping of the Gene for X-Linked Liver Glycogenosis due to Phosphorylase Kinase Deficiency to Human Chromosome Region Xp22," Genomics 9:565-569 (1991); M. W. Kilimann, "Molecular Genetics of Phosphorylase Kinase: cDNA Cloning, Chromosomal Mapping and Isoform Structure," J. Inher. Metab. Dis. 13:435-441 (1990)); the .beta. subunit to chromosome 16 (T. A. Jones et al., "Localization of the Gene Encoding the Catalytic Gamma Subunit of Phosphorylase Kinase to Human Chromosome Bands 7p12-q21," Biochim. Biophys. Acta 1048:24-29 (1990)), and the catalytic (.gamma.) subunit to chromosome 7 (N. J. Lowe & H. B. Ridgeway, "Generalized Pustular Psoriasis Precipitated by Lithium," N. Eng. J. Med. 114:1788-1789 (1978)), and calmodulin (.delta.) subunit to chromosome 10. Aggravation of psoriasis by drugs which lower cAMP levels (M. C. Y. Heng & M. K. Heng, "Beta-Adrenoceptor Antagonist-Induced Psoriasiform Eruption," Int. J. Dermatol. 27:617-627 (1988); M. Sikorsia & J. F. Whitfield, "The Regulatory and Catalytic Subunits of Rat Liver Cyclic AMP-Dependent Protein Kinases Respond Differently to Thyroparathyroidectomy and 1.alpha., 25-Dihydroxyvitamin D3," Biochem. Biophys. Res. Commun. 129:766-772 (1985)) also supports cAMP-dependent protein kinase deficiency and defective deactivation of phosphorylase kinase as a basic mechanism in psoriasiform hyperplasia in psoriasis.
That signal transduction molecules may be involved in triggering the active disease has been suggested by induction of the disease by trauma (E. M. Farber, "Role of Trauma in the Isomorphic Response in Psoriasis," Arch. Dermatol. 91:246-251 (1965); M. C. Y. Heng et al., "Electron Microscopic and Immunocytochemical Study of the Sequence of Events in Psoriatic Plaque Formation After Tape-Stripping," Br. J. Dermatol. 125:548-556 (1991)), as shown by previous reports of elevated levels of calmodulin (W. F. G. Tucker et al., "Biological Active Calmodulin Levels Are Elevated in Both Involved and Uninvolved Epidermis in Psoriasis," J. Invest. Dermatol. 82:298-299 (1984)), and of calmodulin-dependent enzymes such as phospholipase A2 (S. Forster et al., "Characterization and Activity of Phospholipase A2 in Normal Human Epidermis and in Lesion-Free Epidermis of Patients With Psoriasis and Eczema," Br. J. Dermatol. 112:135-147 (1985)), and by elevated prostaglandin F.sub.2.alpha.. (PGF.sub.2.alpha.), as well as other prostaglandins (C. L. Marcelo & J. J. Voorhees, "Cyclic Nucleotides and the Control of Psoriatic Cell Function," Adv. Cyclic Nucleotide Res. 12:1229-1237 (1980); S. Hammarstrom et al., "Increased Concentrations of Free Araclidonic Acid, Prostaglandins E2 and F2.alpha., and of 12-Hydrcxy-5,8,10,14-Eicosatetraenoic Acid (HETE) in Epidermis of Psoriasis: Evidence for Perturbed Regulation of Arachidonic Acid Levels in Psoriasis," Proc. Natl. Acad. Sci. USA 72:5130-5134 (1975)). However, the reasons for reports of variable cAMP levels (G. G. Krueger, "Psoriasis: Current Concepts," in Yearbook of Dermatology (R. L. Dodson & B. H. Thiers, eds., Yearbook Medical Publishers, Inc., Chicago, 1981) pp. 13-70) and Decreased cAMP-Dependent Protein Kinase II Levels (D. E. Brion et al., "Deficiency of Cyclic AMP-Deperdent Protein Kinases in Human Psoriasis," Proc. Natl. Acad. Sci. USA 83:5272-5276 (1986)) are less clear.
The psoriatic plaque is characterized by hyperproliferative epidermal kinetics (E. J. Van Scott & T. M. Ekel, "Kinetics of Hyperplasia in Psoriasis," Arch. Dermatol. 88:373-381 (1963); R. Marks, "Epidermal Activity in the Involved and Uninvolved Skin of Patients with Psoriasis," Br. J. Dermatol. 98:399-404 (1978)), increased polyamine-dependent (N. J. Lowe, "Cutaneous Polyamines in Psoriasis," Br. J. Dermatol. 107:21-25 (1982)) cell cycling with an increased proliferative pool (G. D. Weinstein & J. L. McCollough, "Cytokinetics in Diseases of Epidermal Hyperplasia," Annu. Rev. Med. 24:345-352 (1973); S. Gelfant, "The Cell Cycle In Psoriasis," Br. J. Dermatol. 95:577 (1976); G. L. Grove, "Epidermal Cell Kinetics in Psoriasis," Int. J. Dermatol. 18:111-122 (1979)), followed by increased DNA synthesis (L. Rowe et al., "Mitoses in Normal and Psoriatic Epidermis," Br. J. Dermatol. 98:293-299 (1978)) and mitoses (J. G. Chafouleas et al., "Changes in Calmodulin and Its mRNA Accompany Reentry of Quiescent (GO) Cells Into the Cell Cycle," Cell 36:73-81 (1984)). Polyamine-induced cell cycling involves calcium-dependent (C. Cochet & E. M. Chamber, "Polyamine-Mediated Protein Phosphorylations: A Possible Target of Intracellular Polyamine Reactions," Mol. Cell. Endocrinol. 30:247-266 (1983)) protein phosphorylation (W. L. Combest, "Polyamines Differentially Inhibit Cyclic-AMP Dependent Protein Kinase-Mediated Phosphorylation in the Brain of a Tobacco Hornworm, Manduca sexta," J. Neurochem. 119:1581-1591 (1988)), and ATP generation, which is achieved not directly but through an unknown substrate (W. L. Combest, 1988, supra).
Cell cycling in psoriatic epidermis has been shown additionally to be modulated by epidermal growth factor (EGF) (J. T. Elder et al., "Overexpression of TGF-.alpha. in Psoriatic Epidermis," Science 243: 811-814 (1989); L. B. Nanney et al., "Altered .sup.125 I!-Epidermal Growth Factor Binding and Receptor Distribution in Psoriasis," J. Invest. Dermatol.. 86: 260-266 (1986)).
Another hallmark of psoriasis is blood vessel abnormalities, which precede the development of overt histological psoriasis. High endothelial venules (HEVS) exist in psoriatic skin, and tannic acid staining material is present in the intercellular spaces between adjacent endothelial cells of the HEVs in psoriatic skin. The HEVs appear to be recognized by T8 (CD8) (cytotoxic/suppressor) lymphocytes, as the presence of HEVs was found to be related to the presence of T8 (CD8) lymphocytes in the epidermis. The tannic acid staining material may serve as a marker for HEVs recognized by the T8 (CD8) lymphocyte subset. The prior existence of HEVs in uninvolved psoriatic skin could account for the rapid egress of T8 (CD8) lymphocytes from the vasculature to the epidermis in response to trauma (M. C. Y. Heng et al., "High Endothelial Venules in Involved and Uninvolved Psoriatic Skin: Recognition by Homing Receptors on Cytotoxic T Lymphocytes," Br. J. Dermatol. 118: 315-326 (1988).
Psoriatic lesions can be induced by trauma in psoriatic individuals. Among the earliest changes noted in events leading to the formation of a psoriatic Flaque induced by tape-stripping was increased mobility of the epidermal Langerhans cells across the basement membrane, evidence of Langerhans cell-lymphocyte interaction, ard increased Langerhans cell activity or cytotoxicity. Collections of epidermal lymphocytes showing the features of blastoid transformation while in contact with processes from activated Langerhans cells suggest the involvement of Ia antigens in this process. These findings are consistent with an increased immune responsiveness to trauma, controlled by genes located at the HLA-D locus of the major histocompatibility complex, and mediated by enhanced cellular interactions (M. C. Y. Heng et al., "The Sequence of Events in Psoriatic Plaque Formation After Tape-Stripping," Br. J. Dermatol. 112: 517-532 (1985)).
There is some evidence that enhanced terminal differentiation of psoriatic keratinocytes, as shown by the increased expression of L-fucose specific binding sites on psoriatic keratinocytes (H. Roelfzema et al., "Studies on the Plasma Membrane of Normal and Psoriatic Keratinocytes. IV. Characterization of Glycoconjugates," Br. J. Dermatol. 105:509-516 (1981); M. C. Y. Heng et al., "Expression of the L-Fucose Moiety on Epidermal Keratinocytes in Psoriasis Induced by the Koebner Phenomenon," Br. J. Dermatol. 126:575-581 (1992); J. D. Zieski & I. A. Bernstein, "Modification of Cell Surface Glycoprotein: Addition of Fucosyl Residues During Epidermal Differentiation," J. Cell. Biol. 95:626-631 (1982)), may be equally important in the psoriatic process. Enhanced terminal differentiation has been shown to be an essential feature of the positive Koebner phenomenon, and L-fucose expression on epidermal keratinocytes is observed on keratinocytes undergoing terminal differentiation, such as in the Koebner phenomenon.
Biochemically, the process of terminal differentiation consists of a series of calcium-dependent reactions, all requiring energy and triggered by an influx of calcium into the keratinocyte (B. A. Dale et al., "Identification of Filaggrin in Cultured Mouse Keratinocytes and its Regulation by Calcium," J. Invest. Dermatol. 81:90s-95s (1983); H. Hennings et al., "Calcium Regulation of Growth and Differentiation of Mouse Epidermal Cells in Culture," Cell 19:245-254 (1980); S. T. Boyce & R. G. Ham, "Calcium Regulated Differentiation of Normal Human Keratinocytes in Chemically Defined Clonal Culture and Serum Free Serial Culture," J. Invest. Dermatol. 81:33s-40s (1983); C. K. Menon & P. M. Elias, "Ionic Calcium Reservoirs in Mammalian Epidermis: Ultrastructural Localization With Ion-Capture Cytochemistry," J. Invest. Dermatol. 84:508-512 (1985); P. Cohen, "The Role of cAMP-Dependent Protein Kinase in the Regulation of Glycogen Metabolism in Mammalian Skeletal Muscle," Curr. Top. Cell. Regulat. 14:117-196 (1978)).
Despite the increasing knowledge of the biochemical and genetic origins of psoriasis and the molecular events associated with the excess proliferation and terminal differentiation of epidermal cells that is the mark of the disease, effective treatments for psoriasis are still elusive. The disease is often subject to chronic and repeated remissions and exacerbations, which can be triggered by stress or exposure to environmental factors.
Because of the chronic nature of the disease and the necessity to continue treatment over long periods of time, new treatments of greater efficacy and lacking side effects are greatly desired. Preferably, such new treatments would be able to control the disease and prevent exacerbations caused by environmental factors, stress, and other factors that are not yet understood.